Nasal administration

ABSTRACT

A delivery device for and method of delivering a powdered substance, in particular a triptan, such as sumatriptan, to the posterior region of a nasal cavity of a subject, in particular for the treatment of headaches, for example, cluster headaches and migraine, and neuropathic pain, the delivery device comprising: a nosepiece for insertion into a nasal cavity of a subject through which the powdered substance is delivered to the posterior region of the nasal cavity of the subject, in particular the upper posterior two thirds of the nasal cavity; and a substance supply unit which is operable to deliver the powdered substance through the nosepiece.

This application is a continuation of application Ser. No. 12/594,365,filed Apr. 30, 2010, which is a national stage of InternationalApplication No. PCT/GB2008/001226, filed Apr. 7, 2008, which claimspriority to Great Britain Application No. 0706744.0, filed Apr. 5, 2007.The disclosures of all applications cited in this paragraph areincorporated herein in their entirety by reference.

The present invention relates to the nasal administration of powderedsubstances, in particular drugs, and in particular substances whichrequire a rapid onset of action, such as in the treatment of pain,including headaches, for example, cluster headaches and migraine, andneuropathic pain.

Referring to FIG. 1( a), the nasal airway 1 comprises the two nasalcavities separated by the nasal septum, which airway 1 includes numerousostia, such as the paranasal sinus ostia 3 and the tubal ostia 5, andolfactory cells, and is lined by the nasal mucosa. The nasal airway 1can communicate with the nasopharynx 7, the oral cavity 9 and the lowerairway 11, with the nasal airway 1 being in selective communication withthe anterior region of the nasopharynx 7 and the oral cavity 9 byopening and closing of the oropharyngeal velum 13. The velum 13, whichis often referred to as the soft palate, is illustrated in solid line inthe closed position, as achieved by providing a certain positivepressure in the oral cavity 9, such as achieved on exhalation throughthe oral cavity 9, and in dashed line in the open position.

The present inventors have surprisingly identified that a rapid systemicuptake can be achieved, as compared to the conventional delivery of anequivalent liquid substance, by the delivery of a powdered substance tothe posterior region of the nasal airway, and in particular the upperposterior two thirds.

The posterior region of the nasal airway is that region which isposterior of the nasal valve NV, as illustrated in FIG. 1( b). The nasalvalve comprises the anterior bony cavum which contains inferiorturbinate erectile tissue and septal erectile tissue, which aresupported respectively by compliant ala tissue and the rigidcartilaginous septum (Cole, P (The Respiratory Role of the UpperAirways, a selective clinical and pathophysiological review. 1993,Mosby-Year Book Inc. ISBN1.55664-390-X)). These elements combine to forma dynamic valve, which extends over several millimeters, that adjustsnasal airflow, and is stabilized by cartilage and bone, modulated byvoluntary muscle and regulated by erectile tissue. The lumen of thenasal valve is the section of narrowest cross-sectional area between theposterior and anterior regions of the nasal airway, and is much longerand narrower dorsally than ventrally, and this lumen defines atriangular entrance which extends to the piriform region of the bonycavum. The nasal valve is lined in its anterior part with transitionalepithelium, with a gradual transition posterior to respiratoryepithelium. The nasal valve and anterior vestibule define roughly theanterior one-third of the nose.

The posterior region of the nasal airway is that region which is linedwith respiratory epithelium, which is ciliated, and olfactoryepithelium, which comprises nerves which extend downwards through thecribiform plate CP from the olfactory bulb, whereas the anterior regionof the nasal airway is that region which is lined with squamousepithelium, which is not ciliated, and transitional epithelium. Theolfactory epithelium extends on both the lateral and medial sides of thenasal airway, and typically extends downwards about 1.5 to 2.5 cm.

The upper posterior region is the region above the inferior meatus IM,as illustrated in FIG. 1( b), and encompasses the middle turbinate, thesinus ostia in infundibulum (ostia to maxillary, frontal and ethmoidalsinuses), the olfactory region, and the upper branches of the trigeminalnerve, and is that region which includes veins which drain to the venoussinuses that surround the brain.

As illustrated in FIG. 1( b), the posterior region of the nasal airwayis the nasal region posterior of an imaginary vertical plane VERT1 whichis located at a position corresponding to one-quarter of the distancebetween the anterior nasal spine AnS, which is a pointed projection atthe anterior extremity of the intermaxillary suture, and the posteriornasal spine PnS, which is the sharp posterior extremity of the nasalcrest of the hard palate and represents the transition between the noseand the nasopharynx, which corresponds to a distance posterior of theanterior nasal spine AnS of between about 13 mm and about 14 mm(Rosenberger, H (Growth and Development of the Naso-Respiratory Area inChildhood, PhD Thesis, Laboratory of Anatomy, School of Medicine,Western Reserve University, Presented to the Annual Meeting of theAmerican Laryngological, Rhinological and Otological Society,Charleston, S.C., USA, 1934) defines the distance between the anteriornasal spine AnS and the posterior nasal spine PnS as being 56 mm ineighteen year old boys and 53.3 mm in eighteen year old girls). As againillustrated in FIG. 1( b), the posterior nasal region is boundedposteriorly by an imaginary vertical plane VERT2 which extends throughthe posterior nasal spine PnS.

As further illustrated in FIG. 1( b), the upper region of the nasalairway is an upper segment of the nasal airway which is bounded by thecribiform plate CP and a horizontal plane HORIZ which is located at aposition corresponding to one-third of the distance between the nasalfloor NF of the nasal airway and the cribiform plate CP, whichcorresponds to a height of typically between about 13 and about 19 mmabove the nasal floor NF (Zacharek, M A et al (Sagittal and CoronalDimensions of the Ethmoid Roof: A Radioanatomic Study, Am J Rhinol 2005,Vol 19, pages 348 to 352) define the distance from the nasal floor NF tothe cribiform plate CP as 46+/−4 mm).

The upper posterior region is thus that upper posterior region which isbounded by the above-defined vertical and horizontal planes VERT1,HORIZ.

The prior art includes a number of comparative studies which compare thepharmacokinetics of substances which are delivered intranasally asliquids and powders. Examples of such studies include the following.

Marttin et al (Nasal absorption of dihydroergotamine from liquid andpowder formulations in rabbits, J. Pharm. Sci., 86(7), pages 802 to 807,1997) compared powder and liquid formulations of dihydroergotamine whichcontained cyclodextrins, and reported the time maximum plasmaconcentration T_(max) to be broadly comparable for a range of powder andliquid formulations.

Matsuyama et al (Improved nasal absoprtion of salmon calcitonin bypowdery formulation with N-acetyl-L-cysteine as a mucolytic agent, J.Cont. Rel., 115, pages 183 to 188, 2006) compared the intranasaladministration of powders and liquids with and without N acetyl cysteinein rats. The powder formulations used in these studies containedethylcellulose and sodium glycocholate as absorption enhancers, and,despite the use of these absorption enhancers, in the formulationslacking N acetyl cysteine, there was no apparent difference in the timemaximum plasma concentration T_(max) between the powder and liquidformulations.

Schipper et al (Nasal insulin delivery with dimethyl beta cyclodextrinas an absorption enhancer in rabbits: powder more effective than liquidformulations, Pharm. Res., 10, pages 682 to 686, 1993) compared theintranasal administration of powders and liquids containing dimethylbeta cyclodextrin as an absorption enhancer, and determined the peakplasma concentration C_(max) for the powder formulation to be greaterthan that for the liquid formulation.

Resta et al (A comparison of sodium cromoglycate nasal solution andpowder in the treatment of allergic rhinitis, Br. J. Clin. Pract., 46,pages 94 to 98, 1992) compared the intranasal administration of powderand solution formulations of sodium cromoglycate in humans, anddetermined the powder formulation to be somewhat more effective.

Pontiroli et al (Nasal administration of glucagons and human calcitoninto healthy subjects: a comparison of powders and spray solutions and ofdifferent enhancing agents, Eur. J. Clin. Pharmacol., 37, pages 427 to430, 1989) compared the intranasal administration of liquid and powderformulations of calcitonin in humans and determined that the absorptionwas comparable in these formulations.

Ishikawa et al (Insoluble Powder Formulation as an Effective Nasal DrugDelivery System, Int. J. Pharm., 224, pages 105 to 114, 2001) reportedthat that permeability of powder and liquid formulations of elcatoninacross excised rabbit mucosa was comparable. In vivo, the powderformulation gave greater bio-availability, which was attributed to theuse of insoluble calcium carbonate in delaying residence time.

The prior art also teaches that the use of powdered substances can leadto reduced bio-availability, which would be understood as a clearprejudice to the use of powdered substances.

Callens et al (Influence of multiple nasal administrations ofbio-adhesive powders on the insulin BA, Int. J. Pharm., 250, pages 415to 422, 1993) studied the intranasal administration of insulin powdersand attributes the longer residence times of powder formulations asbeing disadvantageous, particularly after multiple administrations, inleading to reduced bio-availability.

The prior art also studies the effect of deposition in anterior andposterior regions of the nasal airway.

Pringels et al (Influence of deposition and spray pattern of nasalpowders on insulin bioavailability, Int. J. Pharm., 310(1-2), pages 1 to7, 2006) compared the bioavailability of insulin powders, in a starchformulation, which was delivered to rabbits and reported that depositionposterior to the nasal valve resulted in lower bio-availability thananterior deposition.

This teaching is to the delivery of powdered substances to the anteriorregion of the nasal cavity, in order to provide for improvedbio-availability, and is contrary to the present invention.

In terms of general considerations regarding nasal drug delivery, Behlet al (Effects of physiochemical properties and other factors onsystemic nasal drug delivery, Advanced Drug Delivery Reviews, 29, pages89 to 116, 1998) provides a comprehensive review of systemic nasal drugdelivery.

Also, McMartin, C et al (Analysis of Structural Requirements for theAbsorption of Drugs and Macromolecules from the Nasal Cavity, J. Pharm.Sci., 76(7), 1987, pages 535 to 540) provides a general review of thenasal administration of drugs, in particular those drugs which cannot begiven orally because of linkages which are polar or susceptible todegradation in the GI tract. This review concludes that drugs of up to amolecular weight of 1000 should be administrable without the use ofadjuvants, and that this property could be used for the administrationof polar drugs, for example, peptides.

In one aspect the present invention provides a delivery device fordelivering a powdered substance to the posterior region of a nasalcavity of a subject, the delivery device comprising: a nosepiece forinsertion into a nasal cavity of a subject through which a powderedsubstance is delivered to the posterior region of the nasal cavity ofthe subject; and a substance supply unit which is operable to deliver apowdered substance through the nosepiece.

In one embodiment the substance supply unit comprises acontainer-receiving unit which comprises a container chamber forreceiving a substance-containing container which contains a powderedsubstance to be delivered to the nasal cavity of the subject, and thecontainer chamber includes an outlet which is in fluid communicationwith the nosepiece such as to provide for delivery of the powderedsubstance from the container chamber to the nosepiece.

In one embodiment the container comprises a capsule.

In one embodiment the capsule is formed from a cellulose derivative, andpreferably hydroxypropyl methylcellulose (HPMC).

In another embodiment the capsule is formed from a gelatine derivative.

In one embodiment the capsule is coated with a hydrophobic material, andpreferably parylene.

In one embodiment the nosepiece is configured, when inserted into thenasal cavity, to extend into the nasal valve and provide for expansionthereof.

In one embodiment the nosepiece is configured such as to obstruct thenasal valve.

In one embodiment the nosepiece is configured such as to close the nasalvalve, and thereby substantially prevent deposition of substanceanteriorly of the same.

In one embodiment the delivery device further comprises: a mouthpiecethrough which the subject in use exhales to cause closure of theoropharyngeal velum of the subject.

In one embodiment the delivery device further comprises: a flow channelfluidly connecting the nosepiece and the mouthpiece, whereby exhaled airfrom an exhalation breath is delivered through the nosepiece.

In one embodiment the container chamber includes an inlet which isfluidly connected to the mouthpiece, such that exhaled air from anexhalation breath acts to entrain powdered substance as contained by thecontainer and deliver the same through the nosepiece.

In one embodiment the container-containing member includes a flowpassage in which the container is disposed, such as to be rotatabletherewithin when an air flow is delivered therethrough.

In another embodiment the delivery device further comprises: a flowchannel fluidly connected to the nosepiece through which a gas flow,separate to an exhaled air flow from an exhalation breath of thesubject, is in use delivered to the nosepiece; and a gas supply unit forsupplying a gas flow to the flow channel.

Preferably, the delivery device is configured such that at least 55% ofthe dose as initially deposited in the nasal cavity is deposited in theregion posterior of the nasal valve.

More preferably, the delivery device is configured such that at least60% of the dose as initially deposited in the nasal cavity is depositedin the region posterior of the nasal valve.

Yet more preferably, the delivery device is configured such that atleast 65% of the dose as initially deposited in the nasal cavity isdeposited in the region posterior of the nasal valve.

Still more preferably, the delivery device is configured such that atleast 70% of the dose as initially deposited in the nasal cavity isdeposited in the region posterior of the nasal valve.

Still yet more preferably, the delivery device is configured such thatat least 80% of the dose as initially deposited in the nasal cavity isdeposited in the region posterior of the nasal valve.

Preferably, the delivery device is configured such that at least 35% ofthe dose as initially deposited in the nasal cavity is deposited in theupper posterior two thirds thereof.

More preferably, the delivery device is configured such that at least40% of the dose as initially deposited in the nasal cavity is depositedin the upper posterior two thirds thereof.

Yet more preferably, the delivery device is configured such that atleast 45% of the dose as initially deposited in the nasal cavity isdeposited in the upper posterior two thirds thereof.

Still more preferably, the delivery device is configured such that atleast 50% of the dose as initially deposited in the nasal cavity isdeposited in the upper posterior two thirds thereof.

Yet still more preferably, the delivery device is configured such thatat least 55% of the dose as initially deposited in the nasal cavity isdeposited in the upper posterior two thirds thereof.

In one embodiment the powdered substance contains substantially entirelyactive substance and no introduced excipients, and in particularadjuvants.

In one embodiment the powdered substance has a pH of between about 4.5and about 5.3, and preferably about 4.8.

In one embodiment the powdered substance has a particle sizedistribution of 10% less than about 20 μm, 50% less than about 50 μm and90% less than about 150 μm, and preferably 10% less than about 10 μm,50% less than about 30 μm and 90% less than about 90 μm.

In one embodiment the powdered substance has an untapped bulk density ofbetween about 0.3 g/ml and about 0.5 g/ml, and preferably about 0.4g/ml.

In one embodiment the powdered substance has a tapped bulk density ofbetween about 0.5 g/ml and about 0.75 g/ml, and preferably about 0.63g/ml.

In another aspect the present invention provides a method of deliveringa powdered substance to the posterior region of a nasal cavity of asubject, the method comprising the steps of: fitting a nosepiece to anasal cavity of a subject; and delivering a powdered substance throughthe nosepiece to the posterior region of the nasal cavity of thesubject.

In one embodiment the powdered substance is delivered from a containerchamber which houses a container which contains a powdered substance tobe delivered to the nasal cavity of the subject, and the containerchamber includes an outlet which is in fluid communication with thenosepiece such as to provide for delivery of the powdered substance fromthe container chamber to the nosepiece.

In one embodiment the container comprises a capsule.

In one embodiment the capsule is formed from a cellulose derivative, andpreferably hydroxypropyl methylcellulose (HPMC).

In another embodiment the capsule is formed from a gelatine derivative.

In one embodiment the capsule is coated with a hydrophobic material, andpreferably parylene.

In one embodiment the nosepiece is configured, when inserted into thenasal cavity, to extend into the nasal valve and provide for expansionthereof.

In one embodiment the nosepiece is configured such as to obstruct thenasal valve.

In one embodiment the nosepiece is configured such as to close the nasalvalve, and thereby substantially prevent deposition of substanceanteriorly of the same.

In one embodiment the method further comprises the step of: closing theoropharyngeal velum of the subject.

In one embodiment the method further comprises the step of: the subjectexhaling through a mouthpiece to cause closure of the oropharyngealvelum of the subject.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,whereby exhaled air from an exhalation breath is delivered through thenosepiece.

In one embodiment the container chamber includes an inlet which isfluidly connected to the mouthpiece, such that exhaled air from anexhalation breath acts to entrain powdered substance as contained by thecontainer and deliver the same through the nosepiece.

In one embodiment the container chamber includes a flow passage in whichthe container is disposed, such as to be rotatable therewithin when anair flow is delivered therethrough.

In another embodiment the method further comprises the step of:delivering a gas flow, separate to an exhaled air flow from anexhalation breath of the subject, to the nosepiece.

Preferably, at least 55% of the dose as initially deposited in the nasalcavity is deposited in the region posterior of the nasal valve.

More preferably, at least 60% of the dose as initially deposited in thenasal cavity is deposited in the region posterior of the nasal valve.

Yet more preferably, at least 65% of the dose as initially deposited inthe nasal cavity is deposited in the region posterior of the nasalvalve.

Still more preferably, at least 70% of the dose as initially depositedin the nasal cavity is deposited in the region posterior of the nasalvalve.

Yet still more preferably, at least 80% of the dose as initiallydeposited in the nasal cavity is deposited in the region posterior ofthe nasal valve.

Preferably, at least 35% of the dose as initially deposited in the nasalcavity is deposited in the upper posterior two thirds thereof.

More preferably, at least 40% of the dose as initially deposited in thenasal cavity is deposited in the upper posterior two thirds thereof.

Yet more preferably, at least 45% of the dose as initially deposited inthe nasal cavity is deposited in the upper posterior two thirds thereof.

Still more preferably, at least 50% of the dose as initially depositedin the nasal cavity is deposited in the upper posterior two thirdsthereof.

Yet still more preferably, at least 55% of the dose as initiallydeposited in the nasal cavity is deposited in the upper posterior twothirds thereof.

In one embodiment the powdered substance contains substantially entirelyactive substance and no introduced excipients, and in particularadjuvants.

In one embodiment the powdered substance has a pH of between about 4.5and about 5.3, and preferably about 4.8.

In one embodiment the powdered substance has a particle sizedistribution of 10% less than about 20 μm, 50% less than about 50 μm and90% less than about 150 μm, and preferably 10% less than about 10 μm,50% less than about 30 μm and 90% less than about 90 μm.

In one embodiment the powdered substance has an untapped bulk density ofbetween about 0.3 g/ml and about 0.5 g/ml, and preferably about 0.4g/ml.

In one embodiment the powdered substance has a tapped bulk density ofbetween about 0.5 g/ml and about 0.75 g/ml, and preferably about 0.63g/ml.

In one embodiment the time maximum plasma concentration T_(max) is lessthan about 25 minutes.

In one embodiment the time maximum plasma concentration T_(max) is lessthan about 20 minutes.

In one embodiment the peak plasma concentration C_(max) for the activesubstance is at least 10 ngml⁻¹ for a 10 mg dose of the activesubstance.

In one embodiment the peak plasma concentration C_(max) for the activesubstance is at least 15 ngml⁻¹ for a 20 mg dose of the activesubstance.

Preferably, the ratio of the nasal absorption fraction to totalbio-availability (BA) is greater than about 1.

More preferably, the ratio of the nasal absorption fraction to totalbio-availability (BA) is greater than about 1.5.

Yet more preferably, the ratio of the nasal absorption fraction to totalbio-availability (BA) is greater than about 2.0.

In one embodiment the powdered substance comprises a triptan.

In one embodiment the powdered substance comprises sumatriptan.

In another embodiment the powdered substance comprises one or more ofrisatriptan, naratriptan, eletriptan, frovatriptan and zolmitriptan.

In another embodiment the powdered substance comprises an analgesic.

In one embodiment the powdered substance comprises an opiod.

In another embodiment the powdered substance comprises an ergotamine,such as one or more of dihydroergotamine mesylate, ergonovine maleateand ergotamine tartarate with caffeine.

In a further embodiment the powdered substance comprises one or more offentanyl, oxycondone, hydromorphone, morphine, codeine, ketobemidone andcocaine.

In a further embodiment the powdered substance comprises abenzodiazepine, such as midazolam.

In a yet further embodiment the powdered substance comprises anon-steroidal anti-inflammatory drug (NSAID), such as one or more ofaspirin, ibuprofen, naproxen, indomethacin, diclofenac and ketoprofen.

In a still further embodiment the powdered substance comprises a peptideor protein.

In one embodiment the peptide or protein has a molecular weight greaterthan about 1000.

In one embodiment the powdered substance comprises one or more ofinsulin, including its analogues and derivatives, desmopressin andcalcitonin.

In a yet still further embodiment the powdered substance comprises oneor more of a vaccine, an immunomodulator and an immunostimulator.

In one embodiment the method is for the treatment of pain.

In one embodiment the method is for the treatment of headaches.

In one embodiment the method is for the treatment of cluster headaches.

In another embodiment the method is for the treatment of migraine.

In another embodiment the method is for the treatment of neuropathicpain.

In another embodiment the method is for inducing sedation.

In a further embodiment the method is for the treatment of a partial orfull epilepsy seizure.

In a yet further embodiment the method is for the treatment of a panicdisorder.

In a still further embodiment the method is for the treatment ofinsomnia.

In a still yet further embodiment the method is for the treatment ofjet-lag.

In yet another embodiment the method is for regulating blood glucoselevels.

In still another embodiment the method is for influencing satiety or thesense of satiety.

In yet still another embodiment the method is for delivering amemory-enhancing agent prior to a learning episode.

The present applicant has developed a novel nasal delivery system, asdisclosed in WO-A-2000/051672, the content of which is hereinincorporated by reference, which provides for the delivery of drugs andvaccines in a bi-directional air flow through the two nasal passageswhen connected in series by closure of the oropharyngeal velum.

The present invention will now be described hereinbelow by way ofexample only with reference to the accompanying drawings, in which:

FIG. 1( a) schematically illustrates the anatomy of the upperrespiratory tract of a human subject;

FIG. 1( b) illustrates the segmentation of a nasal cavity in accordancewith a preferred embodiment of the present invention;

FIG. 2 illustrates a nasal delivery device in accordance with oneembodiment of the present invention;

FIG. 3 illustrates the nasal delivery device of FIG. 2, where operativein delivering substance to the nasal cavity of the subject;

FIG. 4 illustrates the time course for the measured blood plasmaconcentrations of sumatriptan for the 10 mg intranasal administration ofthe present invention as employed in Example #1 as compared to historicdata for 10 mg Imitrex® intranasal administration; and

FIG. 5 illustrates median maps for theta and alpha relative energies forthe 10 mg and 20 mg nasal administrations of the present invention andthe 6 mg comparator sub-cut administration as employed in Example #1.

FIGS. 2 and 3 illustrate a nasal delivery device in accordance with oneembodiment of the present invention.

The delivery device comprises a housing 15, a capsule-receiving unit 16for receiving a capsule C, a nosepiece unit 17 for fitting to a nasalcavity of a subject, a mouthpiece unit 19 through which the subjectexhales, and a capsule-piercing mechanism 20, which is operable topierce a capsule C as contained by the capsule-receiving unit 16 andthereby prime the delivery device for operation.

The housing 15 includes a first, nosepiece aperture 21, in thisembodiment at the upper end of the housing 15, which receives thenosepiece unit 17, and a second, lateral aperture 22, in this embodimentin an end wall of the housing 15, through which extends an actuatorbutton 81 of the capsule-piercing mechanism 20, as will be described inmore detail hereinbelow.

The capsule-receiving unit 16 comprises a capsule-receiving member 23,in this embodiment an elongate, upstanding chamber which is disposedopposite the nosepiece aperture 21 in the housing 15, for receiving acapsule C, in this embodiment as contained within a capsule-containingmember 49 of the nosepiece unit 17, as will be described in more detailhereinbelow.

In this embodiment the capsule-receiving member 23 includes an inlet 24and an outlet 25 for providing for an air flow therethrough, with theoutlet 25, as defined by an upper, downstream end of thecapsule-receiving member 23, being adapted to receive thecapsule-containing member 49 of the nosepiece unit 17, such that thecapsule-containing member 49 is a sealing fit within thecapsule-receiving member 23.

The nosepiece unit 17 comprises a main body member 45 which isconfigured to fit in the nosepiece aperture 21 of the housing 15, anosepiece 47 which extends outwardly of the main body member 45 forfitting to the nostril of the subject, and a capsule-containing member49 which extends inwardly of the main body member 45 and contains acapsule C, the contents of which are to be delivered to the nasal cavityof the subject. In this embodiment the capsule C is a hydroxypropylmethylcellulose (HPMC) capsule which contains a particulate substance,such as a powdered substance, and typically a pharmaceutical substance.In other embodiments the capsule C could be formed substantially ofanother cellulose derivative, such as hydroxypropylcellulose,methylcellulose, ethylcellulose and carboxymethylcellulose. In analternative embodiment the capsule C can be formed from a gelatinederivative. In one embodiment the capsule C can be coated with ahydrophobic material, such as parylene.

In this embodiment the nosepiece 47 has a substantially frusto-conicalouter section 53 for guiding the nosepiece unit 17 into a nasal passageof the subject and providing a fluid-tight seal with the nares of thenostril, and includes an inner channel 55, here of substantiallycylindrical section, through which substance is delivered to a posteriorregion of the nasal passage of the subject, in this embodiment an upperposterior region as bounded by a vertical plane which is locatedposterior of the anterior nasal spine AnS at a position corresponding toone-quarter of the distance between the anterior and posterior nasalspines AnS, PnS and a horizontal plane which is located above the nasalfloor at a height one-third of the distance between the nasal floor andthe cribiform plate. As discussed hereinabove, the present inventorshave recognized that an increased delivery of powdered substance to theupper posterior region of the nasal passage surprisingly provides for avery rapid onset of action as compared to the conventional nasaladministration of a liquid substance.

In this embodiment the nosepiece 47 is configured to deliver asignificant fraction of substance to the upper posterior region of thenasal passage, here an initial deposition of greater than 30% of thedelivered dose.

In this embodiment the nosepiece 47, in providing a fluid-tight sealwith the nostril of the subject, provides for bi-directional deliverythrough the nasal airway of the subject, as disclosed in the applicant'searlier WO-A-2000/051672. In another embodiment, however, the nosepiece47 need not provide a sealing fit, thus encompassing delivery to thenasal cavity, but not necessarily bi-directional delivery.

In this embodiment the nosepiece 47 includes a trap element 57,typically a perforated or mesh element, for preventing any foreignmatter, such as a part of the capsule C, which is above a predeterminedsize from passing through the nosepiece 47 and into the nasal cavity ofthe subject.

The capsule-containing member 49 includes an elongate flow passage 63,in this embodiment cylindrical in shape, in which the capsule C isoriented axially therealong such as to be rotatable therewithin when anair flow is delivered therethrough, and an inlet aperture 65 in fluidcommunication with one, the downstream, end of the flow passage 63,which inlet aperture 65 provides a flow restriction to an air flow asdelivered therethrough and acts as a seat for one, the lower, end of thecapsule C prior to the delivery of an air flow through the flow passage63.

The capsule-containing member 49 further includes a plurality of, inthis embodiment first and second piercing apertures 71, 73 in a lateralwall thereof for enabling the capsule C to be pierced at locationsspaced along the axial length thereof. In this embodiment the first,lower aperture 71 is located such that the capsule C is pierced at alocation above the height of the dose of substance as contained therebywhen the lower end of the capsule C is seated in the inlet aperture 65of the flow passage 63. In this way, the dose of substance as containedby the capsule C is not released into the flow passage 63 until an airflow is delivered through the flow passage 63.

In this embodiment the nosepiece unit 17 is provided as a replaceableunit which is replaced following each operation of the delivery device.In this embodiment the nosepiece unit 17 can be packaged in air-tightpackaging, for example, an aluminum foil package.

The mouthpiece unit 19 comprises a mouthpiece 77, in this embodiment asgripped in the lips of the subject, through which the subject exhales todeliver an entraining air flow through the capsule-receiving unit 16,and an air chamber 78, in this embodiment an elongate tubular section,which fluidly connects the mouthpiece 77 and the capsule-receiving unit16.

In this embodiment the air chamber 78 has a greater volume than thecapsule-receiving member 23 of the capsule-receiving unit 16, andpreferably has a volume at least twice that of the capsule-receivingmember 23.

In this embodiment the air chamber 78 incorporates a temperatureregulator 79, here formed as a condenser for cooling the exhaled airflow, at least at the upstream end thereof. With this configuration, theexhaled air flow is cooled during exhalation.

In this embodiment the temperature regulator 79 comprises a labyrinthinestructure. In another embodiment the temperature regulator 79 could beprovided by a filter element, which could also act as a microbiologicalfilter.

In one embodiment the temperature regulator 79 could include means fordrying the condensate as collected therein when the delivery device isnot in use.

In one embodiment the air chamber 78 is removable, such as to allow forcleaning or replacement.

This arrangement has been found to provide for reliable operation of thedelivery device, in delivering substance from the capsule C. The presentinventors have established that the provision of moist exhaled airdirectly to the capsule C can sometimes prevent the required rotation ofthe capsule C, and thereby prevent proper release of the substance ascontained thereby. By providing a volume of cooler air, and arrangingfor that volume of cooler air to be delivered initially in a burst, therequired rotation of the capsule C is seen repeatedly.

The capsule-piercing mechanism 20 comprises an actuator button 81 whichextends through the lateral aperture 22 in the housing 15 such as toallow for operation by the subject, a plurality of, in this embodimentfirst and second piercing elements 83, 85 which are supported by theactuator button 81 and extend forwardly thereof, such that, ondepression of the actuator button 81 from a retracted position to anextended position, the piercing elements 83, 85 are driven throughrespective ones of the piercing apertures 71, 73 in the lateral wall ofthe capsule-containing member 49 to pierce the capsule C.

In this embodiment the capsule-piercing mechanism 20 includes aresilient element 87 which acts to bias the actuator button 81 outwardlytowards the retracted position, such that, following depression of theactuator button 81 to pierce the capsule C, the actuator button 81 isreturned to the retracted position. In this embodiment the resilientelement 87 is formed as an integral part of the actuator button 81, butin other embodiments could be provided by a separate element, such as acompression spring.

Operation of the delivery device will now be described hereinbelow.

Firstly, taking the delivery device in hand, and with a nosepiece unit17 inserted in the housing 15, the subject depresses the actuator button81 of the capsule-piercing mechanism 20 such as to pierce the capsule Cas contained in the capsule-containing member 49.

By depressing the actuator button 81, the capsule C is pierced by thepiercing elements 83, 85 at two locations spaced along the axial lengththereof. In this embodiment the first, lower piercing element 83 acts topierce the capsule C at a location just above the height of thesubstance as contained by the capsule C, the capsule C only being partfilled, and the second, upper piercing element 85 acts to pierce theupper, distal end of the capsule C.

The actuator button 81 is then released, which causes the actuatorbutton 81 to be returned to the retracted position under the bias of thebiasing element 87. In this way, the delivery device is primed and readyfor use.

The subject then inserts the nosepiece 47 into one of his/her nasalpassages until the nosepiece 47 abuts the nares of the nostril such asto establish a fluid-tight seal therewith, at which point the distal endof the nosepiece 47 extends about 2 cm into the nasal passage of thesubject, and grips the mouthpiece 77 in his or her lips.

The subject then begins to exhale through the mouthpiece 47, whichexhalation acts to close the oropharyngeal velum of the subject anddrive an air flow through the nasal airway of the subject, with the airflow passing into the one nasal passage, around the posterior margin ofthe nasal septum and out of the other nasal passage, thereby achieving abi-directional air flow through the nasal airway of the subject.

When the subject exhales with sufficient force, the capsule C is liftedfrom the seat as defined by the inlet aperture 65 of thecapsule-containing member 49 and the capsule C is rotated, whichrotation acts to release the substance from within the capsule C whichis entrained by the exhaled air flow and delivered to the posteriorregion of the nasal cavity of the subject. With continued exhalation,the capsule C continues to rotate.

This operation of the delivery device can be repeated with a new capsuleC. In this embodiment the entire nosepiece unit 17 is replaced, but inother embodiments either the capsule-containing member 49 or just thecapsule C could be replaced.

The present invention will now be described hereinbelow with referenceto the following non-limiting Examples.

EXAMPLE #1

The purpose of this study was to study the pharmacokinetics ofsumatriptan where intranasally delivered using the above-describedbi-directional nasal administration system.

In this study, twelve healthy subjects were studied.

In separate sessions, the subjects received 10 mg and 20 mg ofsumatriptan base by the bi-directional administration system of theabove-described embodiment, from which a powdered sumatriptanformulation was nasally administered, with 20 mg of the sumatriptan basebeing delivered in two successive 10 mg doses through the respectivenostrils of the subjects, and 6 mg of sumatriptan base (IMIGRAN®Injection pre-filled syringe as available from GlaxoSmithKline) bysub-cut administration.

In this study, the sumatriptan administrations were administered 15minutes prior to the administration of glyceryltrinitrate (GTN), whichallowed the effect on quantitative wake EEG to be studied in subjectssuffering from migraine, where GTN is expected to induce migraine in 75%of subjects who have a history of migraine.

The powdered sumatriptan formulation was contained in an HPMC capsuleand comprised a 10 mg dose of micronized sumatriptan succinate powderand contained no excipients, such as adjuvants.

The sumatriptan succinate powder has a pH (1% w/v in water) of 4.77. Ina preferred embodiment the sumatriptan succinate powder has a pH ofbetween about 4.5 and about 5.3, and preferably about 4.8.

The sumatriptan succinate powder has a particle size distribution of 10%less than 8.08 μm, 50% less than 29.77 μm and 90% less than 88.54 μm.

In a preferred embodiment the sumatriptan succinate powder has aparticle size distribution of 10% less than about 20 μm, 50% less thanabout 50 μm and 90% less than about 150 μm, and preferably 10% less thanabout 10 μm, 50% less than about 30 μm and 90% less than about 90 μm.

The sumatriptan succinate powder has an untapped bulk density of 0.415g/ml and a tapped bulk density of 0.632 g/ml. In a preferred embodimentthe sumatriptan succinate powder has an untapped bulk density of betweenabout 0.3 g/ml and about 0.5 g/ml, and preferably about 0.4 g/ml. In apreferred embodiment the sumatriptan succinate powder has a tapped bulkdensity of between about 0.5 g/ml and about 0.75 g/ml, and preferablyabout 0.63 g/ml.

Venous blood samples, each having a volume of 5 ml, were drawn justprior to administration and at 5, 10, 15, 20, 30, 40, 50, 60, 70, 80,90, 120, 240, 360, 480 and 720 minutes after administration, and theblood plasma concentration of sumatriptan was determined.

From these measured blood plasma concentrations, average values for thetime maximum plasma concentration T_(max), the peak plasma concentrationC_(max), the area under the curve (AUC) at times 20, 30, 60 and 120minutes and ∞, which assumes a zero plasma concentration at 12 hours,and the bio-availability BA were determined for evaluable subjects, asset out in Table I hereinbelow. For comparison, the correspondingpharmacokinetic parameters for the intranasal administration of liquidsumatriptan succinate sprays (10 mg and 20 mg sumatriptan base)(Imitrex® as available from GlaxoSmithKline). The historical data sourcefor the Imitrex® nasal spray is the NDA (#20-626), Study #2a, assubmitted by Glaxo Wellcome Inc. to the FDA, USA.

TABLE I 10 mg 20 mg 6 mg 10 mg 20 mg Invention Invention Sub-Cut ImitrexImitrex T_(max)/ 20 20 10 90 90 min C_(max)/ 10.5 15.9 87.4 7.2 12.8 ngml⁻¹ C₂₀/ 10.5 15.9 66.4 4.2 7.1 ng ml⁻¹ AUC₁₂₀/ 800 1350 4473 690 1182ng min ml⁻¹ AUC_(∞)/ 2137 3105 7467 1734 3375 ng min ml⁻¹ AUC₆₀/ 474 7643278 278 477 ng min ml⁻¹ AUC₃₀/ 236 372 1999 97 172 ng min ml⁻¹ AUC₂₀/136 215 1372 48 93 ng min ml⁻¹ BA/% 17.2 12.5 100 13.9 13.6

As can be seen, the nasal administration of the present invention showsa significantly greater peak plasma concentration C_(max) as comparedwith the existing Imitrex® nasal administration system having the samenominal amount of succinate base, and the concentration at twentyminutes C₂₀ is more than twice the concentration achieved by theexisting Imitrex® nasal administration system.

In fact, the nasal administration system of the present invention hasbeen established, by gamma-scintigraphic studies (in vivo and in vitro),to emit approximately 70% of the dose as contained in the capsule C, andeven with an overage of 5% which is present in the capsule C, the actualamount of succinate base which is delivered by the nasal administrationsystem of the present invention is about 8 mg for a 10 mg nominal and 16mg for a 20 mg nominal. Thus, even more markedly improved results arepredicted as compared with the existing Imitrex® nasal administrationsystem on a dose-for-dose basis.

In addition, the nasal administration of the present invention shows amarkedly shorter time maximum plasma concentration T_(max) as comparedto the existing Imitrex® nasal administration system having the samenominal amount of succinate base. In the present invention, the timemaximum plasma concentration T_(max) is about 20 minutes, which is about70 minutes faster than that achieved with the conventional Imitrex®nasal administration system, and is approaching that of sub-cutdelivery.

This markedly increased time maximum plasma concentration T_(max) lendsthe present invention to indications where a rapid onset of action isrequired. In the present Example, this event is migraine, but thepresent invention can be utilized to treat pain in general, includingother headaches, such as cluster headaches, and neuropathic pain, toinduce sedation, to ameliorate or abort another CNS event, to abort apartial or full epilepsy seizure, to treat a panic disorder, to treatinsomnia, to treat jet-lag, to regulate blood glucose levels, toinfluence satiety or the sense of satiety, or to deliver amemory-enhancing agent prior to a learning episode.

Further, in the nasal administration of the present invention, the areaunder the curve to 30 minutes (AUC₃₀) is greater than twice thatachieved with the conventional Imitrex® nasal administration system andapproaching 2.5 times greater for the 10 mg nominal dose.

Still further, in the nasal administration of the present invention, thearea under the curve to 20 minutes (AUC₂₀) is greater than twice thatachieved with the conventional Imitrex® nasal administration system andapproaching three times greater for the 10 mg nominal dose.

In addition, with the nasal administration of the present invention, thetime course for the measured blood plasma concentration followingadministration shows a bifurcated trace, which has two peaks and isindicative of a hybrid absorption mechanism, with the early absorptionbeing nasal absorption and the later, delayed absorption being oral orGI absorption. Studies have shown that oral absorption is very limitedwithin a period of 20 minutes following administration, and thus it canbe assumed that the absorption in the period to 20 minutes followingadministration relates essentially only to nasal absorption.

On this basis, the bi-directional administration of the presentinvention provides a significantly greater ratio of nasal absorptionfraction to total bioavailability (BA), which clearly demonstrates theimproved pharmacokinetics of the present invention. The presentinvention achieves a ratio of about 2.21, which compares with a ratio ofabout 0.71 for the conventional Imitrex® nasal administration system,where the nasal absorption fraction of the total BA is about 10%(Fuseau, E et al, Clinical Pharmacokinetics of Intranasal Sumatriptan,Drug Deposition, 41(11), 2002, pages 801 to 811) and the total BA afternasal administration is about 14%. From data available for othertriptans delivered both as a nasal spray and orally (Goadsby, P,Zolmitriptan Intranasal: A Review of the Pharmacokinetics and ClinicalEfficacy, Headache, 2006, 46, pages 138 to 149), zolmitriptan has aratio of about 0.75, where the fraction of nasal absorption is about 30%and the total BA is about 40%. In this study, the fraction absorbednasally was calculated by preventing absorption via the GI tract throughthe use of charcoal.

The markedly-improved pharmacokinetics of the nasal administration ofthe present invention is clearly shown in FIG. 3, which shows the timecourse for the averaged measured blood plasma concentration followingadministration of the sumatriptan succinate powder (10 mg sumatriptanbase) by the bi-directional nasal administration of the presentinvention as compared to the corresponding historic averaged measuredblood plasma concentration following intranasal administration of the 10mg sumatriptan base Imitrex® nasal spray administration system.

The efficacy of the present invention is particularly surprising as theformulation of the present invention includes no absorption enhancer ormuco-adhesive.

In the EEG analysis, the EEG profiles for the subjects when treated withthe 10 mg and 20 mg intranasal administration of the present inventionwere broadly similar to the 6 mg sub-cut administration.

Previously, Thomaides, T et al, EEG and topographic frequency analysisin migraine attack before and after sumatriptan infusion, Headache, 36,pages 111 to 114, 1996, have determined that the main effects on the EEGassociated with GTN-induced headaches are significant increases inrelative values for the delta and theta frequency bands, with decreasesin the alpha and beta frequency bands not reaching significance.

The treatment effects on the EEG relative energy parameter for eachrecording time are summarized in Table II hereinbelow for each frequencyband (FB). A significant (p<0.05 for sufficiently large number of scalpelectrodes) IMP drug to comparator increase is indicated by a closedarrow, and a significant IMP drug to comparator decrease is indicated byan open arrow. An arrow between brackets indicates a statistical trend(4-5 electrodes display p<0.05).

TABLE II Sumatriptan Intranasal 10 mg 20 mg FB Invention Invention time(min) Δ

α β Δ

α β First 10 (↑) (

) ↑

20 ↑

(↑)

30 ↑ 40

50 60 70

80 90 2 h

4 h 6 h 8 h

As regards the theta relative energy, increases in theta relative energywere observed, as compared with the 6 mg sub-cut comparatoradministration. The largest differences with active comparator, whichoccurred over almost the entire right half and left posterior scalp from20 to 40 minutes, were observed for the 10 mg administration, and thesedifferences were less pronounced for the 20 mg administration.

As regards the delta relative energy, increases in the delta relativeenergy were more transient in the first 10 minutes for the 10 mg and 20mg administrations, but more pronounced for the 20 mg administration.

As regards the alpha relative energy, both the 10 mg and 20 mgadministrations decreased the alpha relative energy for a duration of 20minutes over large portions of the anterior scalp, and additionally overthe period from 30 to 40 minutes for the 20 mg administration.

Only few unsystematic modifications were observed in the absolutefrequency band energies. For the additional parameters, it is worthwhileto note that the ASI, a measure of cortical arousal, was decreased forboth the mg and 20 mg administrations over large portions of theanterior scalp and displayed between 10 and 40 minutes, in additionspreading over posterior scalp regions for the 20 mg administration.

FIG. 4 illustrates median maps for theta and alpha relative energies forthe 10 mg and 20 mg nasal administrations of the present invention andthe 6 mg comparator sub-cut administration.

As illustrated, in the present study, the most salient effects of the 6mg sub-cut administration were in sustained reductions from 0 to 40minutes in theta activity (row 3), mostly in relative spectralcontributions, and this was accompanied for a period of about half anhour by increased relative beta contributions. In addition, there weresome signs of decreased delta activity (absolute and relative) butlittle effects in alpha activity emerged, but noting the trends foroccipital increases (row 6). Overall, the best EEG-markers reflectingthe restoring potential of sumatriptan are the relative energy values.

In the present study, pre-treatment with the 6 mg sub-cut administrationcompletely prevented the excess in theta induced by sublingual GTN andresulted in depressed theta for 40 minutes. This is in agreement withstudies by others. Indeed, in subjects in which an excess by more than15% of theta (delta only a few percent) had been induced by the GTNchallenge, this effect was reversed within 30 minutes after treatmentwith sumatriptan pharmacotherapy. And, when given via the intranasalroute of administration, the 10 mg and 20 mg nasal administrations ofsumatriptan powder induced, coarsely speaking, a similar EEG profile asthe sub-cut comparator.

The fact that the nasal administrations of the present invention providea similar EEG profile as the sub-cut comparator is particularlysurprising given the very large differences in the C_(max) values forthe nasal administrations of the present invention (10.5 and 15.9) ascompared to the sub-cut comparator (87.4). The reason for thissurprising result is not known, but the present inventors speculate thatthere could be a number of reasons. Firstly, it is known that the rateof abruption is apparently more important than the extent of absorption(Fox, W, Onset of Effect of 5-HT1B/1D Agonists: A Model withPharmacokinetic Validation, Headache, 44, 2004, pages 142 to 147), andthe rate of absorption of the sumatriptan powder of the presentinvention is similar to the sub-cut comparator and much faster than thatof the conventional Imitrex® nasal administration system. Anotherpossible reason is a direct nose-to-brain absorption mechanism, whichhas been shown in animal studies. A further possible reason isabsorption through “counter current” transport via the sinus cavernousand the carotid artery, and, whilst sumatriptan passes the BBB poorly,sumatriptan is able to pass the BBB to some extent. A still furtherpossible reason is direct or indirect action via the trigeminal andolfactory nerves, which is involved in the pathogenesis of migraine.

EXAMPLE #2

This study provides for characterization of the deposition as achievedby the nasal administration system of the present invention as used inthe above-described study.

In this study, eight healthy subjects were studied.

In separate sessions, the subjects each received a test powderformulation, comprising radio-labelled lactose, using the nasaladministration system of the present invention.

The lactose powder, as supplied by Friesland Foods Domo (Zwolle, TheNetherlands), had a nominal mean particle size of 15 μm, with 10% havinga particle size of less than 3 μm, 50% having a particle size less than15 μm and 90% having a particle size less than 38 μm.

The lactose powder was “hot” radio-labelled with technetium 99Tc, usingthe labelling procedure disclosed in Karhu, M et al, InternationalJournal of Pharmaceutics, 196, 2000, pages 95 to 103 (2.1—Labelling oflactose particles). In this procedure, the lactose powder was dispensedin a lead box with a HEPA-filtered air stream and using an aseptictechnique.

The deposition of the test powder in the nasal cavity was imaged using ascintillation camera system, here a VERTEX camera as supplied by ADACLaboratories (USA) which was equipped with a low energy parallel holehigh resolution VXGP collimator.

The powder was administered with the subjects sitting in the uprightposition, and, following administration, the subjects sat back such thatthe floor of the nasal cavity was projected at between 30 and 45 degreeswith respect to the y-axis of the camera detector. This re-positioningtook approximately 1 minute from the dose administration and imaging wasinitiated immediately thereafter. A total of 16 images, each containing128×128 pixels, were acquired at two minute intervals. The subjects wereinstructed not to sniff during the imaging procedure.

As a consequence of the variation in administered activity, the acquiredimages were normalized so that the first image in each series, whichrepresents the initial deposition, had a total image intensity equal to100,000 within a region drawn around the nose as appearing in thecumulative images. As the floor of the nose and the curvature of thepharynx were clearly visible in the cumulative images as derived fromeach of the series, each series of images could conveniently be aligned.

Nasal dimensions were measured by acoustic rhinometry using Rhin2000anatomic nose adaptors as supplied by RhinoMetrics (Lynge, Denmark), toverify normal nasal dimensions and to assist in nasal segmentation.Acoustic rhinometry identified the location of the minimalcross-sectional area corresponding to the head of the inferiorturbinate, the head of the middle turbinate and the transition to theepipharynx.

In order to allow for characterization of the deposition, the noseregion was segmented into six rectangular nasal regions, as illustratedin FIG. 1( b), namely, a lower anterior region (LA), a mid anteriorregion (MA), an upper anterior region (UA), a lower posterior region(LP), a mid posterior region (MP) and an upper posterior region (UP),and one pharyngeal region.

The vertical segmentation VERT1 which defines the anterior and posteriorsegments is at a point just posterior to the anterior limitation of theinferior turbinate, and the vertical segmentation VERT2, which definesthe posterior nasal segment and the nasopharynx is at the posteriormargin of the inferior turbinate. In this embodiment, for the purposesof the detection analysis, the anterior bound of the anterior segmentwas set at 15 pixels anterior to the vertical segmentation VERT1 and theposterior bound of the nasopharynx region was set at 15 pixels posteriorto the vertical segmentation VERT2.

The horizontal segmentation HORIZ1, HORIZ2 which define the lower, midand upper vertical segments are at heights of one-thirds and two-thirdsof the distance between the lower and upper boundaries of the nasalcavity as defined by the nasal floor and the cribiform plate. In thisembodiment the nasal floor was determined to be about 4 mm (c2 pixels)above a radio-labelled marker at the palette in the oral cavity, and theheight of the nasal cavity was determined from the location of theolfactory bulb, which was determined to be between 38 and 45 mm (c18-21pixels) depending upon the subject.

Table III below shows the mean values for the initial deposition in thesix nasal segments and the nasopharynx, as represented by the first inthe series of images for each of the subjects.

TABLE III Image Percentage (%) Upper Anterior (UA) 1.7 Mid Anterior (MA)10.7 Lower Anterior (LA) 5.9 Upper Posterior (UP) 17.4 Mid Posterior(MP) 41.4 Lower Posterior (LP) 20.9 Nasopharynx (NP) 2.0

As can be seen, the bi-directional administration system provides forinitial deposition of greater than 80% beyond the nasal valve of thetotal dose as deposited in the nasal cavity, and greater than 57% of thetotal dose as deposited in the nasal cavity is deposited in the upperposterior two thirds of the nasal cavity. This deposition patterncontrasts markedly with existing nasal delivery devices, where between50 and 80% of the delivered dose is deposited anterior of the nasalvalve.

The present inventors attribute this deposition pattern as an importantcontributing factor to the surprisingly enhanced efficacy as achieved inthe study of Example #1. As mentioned hereinabove, the present inventorspostulate that deposition in the upper posterior region, and inparticular the upper posterior two thirds, which has a single-cellmucosal layer, allows for a direct nose-to-brain absorption mechanism,absorption through “counter current” transport via the sinus cavernousand the carotid artery, and direct or indirect action via the olfactoryand trigeminal nerves, which is involved in the pathogenesis ofmigraine.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

The present invention has been exemplified in relation to sumatriptan,but it will be understood that the present invention has application tomany other substances, including other triptans, such as risatriptan,naratriptan, eletriptan, frovatriptan and zolmitriptan, and otheranalgesics, such as ergotamines, including dihydroergotamine mesylate,ergonovine maleate and ergotamine tartarate with caffeine, fentanyl,oxycondone, hydromorphone, morphine, codeine, ketobbemidone, cocaine andopiods in general.

The present invention also has application to benzodiazepines, such asmidazolam.

The present invention further has application in relation tonon-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin,ibuprofen, naproxen, indomethacin, diclofenac and ketoprofen.

The present invention still further has application in relation toproteins and peptides, in particular having a molecular weight greaterthan 1000 g/mol, which typically have a very low oral bio-availability,often less than 1%. Particular examples include insulin, including itsanalogues and derivatives, desmopressin and calcitonin.

The present invention yet still further has application in relation topowder vaccines, immunomodulators and immunostimulators.

In summary, the present invention has application in relation to thefollowing broad definitions of molecules.

-   (I) Small molecules (<1000) with relatively fast nasal absorption    and high nasal BA, such as fentanyl, midazolam and oxycodone. The    present invention suggests far more rapid CNS effects than compared    to the prior art nasal administration systems, which could be    because of differences between arterial and venous concentrations,    where arterial absorption is between about 25% and 50% greater than    venous absorption, possible “counter current” transport to the sinus    cavernous and the carotid artery, which must pass the BBB, which has    been shown to be about 25% greater in animal studies, and possible    direct N2B transport along the olfactory and trigeminal nerves    (Einer-Jensen, N et al, Pharmacy. Toxicol., 87(6), 2000, pages 276    to 278, Einer-Jensen, N et al, Exp. Brain Res., 130(2), 2000, pages    216 to 220, and Dale, O et al, Intranasal Midazolam: a comparison of    two delivery devices in human volunteers, J. Pharmacy and    Pharmacology, 58, 2006, pages 1311 to 1318). N2B transport and    clinical effects via the trigeminal nerves are not, however,    necessarily reflected in the traditional PK profile.-   (II) Small and medium sized molecules with relatively poor BA, such    as sumatriptan and zolmitriptan. For the sumatriptan powder of the    present invention, sumatriptan passes the BBB relatively poorly, but    animal studies suggest that sumatriptan can be transported directly    to the brain by direct N2B mechanisms (Gladstone, J P, Newer    formulations of triptans: Advances in migraine treatment, Drugs, 63,    2003, pages 2285 to 2305). The present invention provides for    increased absorption, which is particularly relevant where rapid    absorption and a fast onset of action are desirable. The present    invention suggests more rapid CNS effects, which could be because of    possible direct N2B uptake, possible “counter current” transport to    the sinus cavernous and the carotid artery, where the molecule is    able to pass the BBB, and possible direct N2B transport along the    olfactory and trigeminal nerves.-   (III) Larger molecules (>1000), including peptides and proteins,    which have low nasal BA, typically between about 3 and 15%, and very    poor oral BA, typically less than 1%, because of degradation in the    GI tract. The present invention, in providing a powder formulation,    is particularly suited to the delivery of peptides and proteins,    where the powder can provide for improved nasal absorption, but also    can have improved stability. For these substances, it is postulated    that there may be a dedicated transport mechanism along the    olfactory and trigeminal nerves directly to the cerebral structures,    which is not via the CSF. As such, measurements from the CSF may not    show the presence of active substance, but a substantial effect may    be present in the brain and exert clinical effects, as exemplified    in a recent study (Thorne, R G et al, Delivery of insulin-like    growth factor-I to the rat brain and spinal cord along olfactory and    trigeminal pathways following intranasal administration,    Neuroscience, 127(2), 2004, pages 481 to 496).

The invention claimed is:
 1. A nasal delivery device for delivering gpowdered sumatriptan substance to a nasal cavity of a human subject, thedelivery device comprising: a nosepiece for fitting to the nasal cavityof the subject, and a capsule-containing member which contains acapsule, the capsule containing the powdered sumatriptan substance to bedelivered to the nasal cavity of the subject, wherein thecapsule-containing member includes a flow passage in which the capsuleis disposed to be rotatable therewithin when an air flow is deliveredtherethrough, the flow passage including an inlet and an outlet which isin fluid communication with the nosepiece, wherein the device isconfigured such that, when the nosepiece is fitted to the nasal cavityof the subject, oral exhalation by the subject through the nosepieceacts to close the velum of the subject and drive an air flow through thenasal cavity, with the air flow passing into one nasal passage and outthe other nasal passage, thereby achieving a bi-directional air flow,and wherein the powdered sumatriptan substance has a particle sizedistribution of 10% less than about 20 μm, 50% less than about 50 μm and90% less than about 150 μm.
 2. The delivery device of claim 1, whereinthe inlet of the flow passage includes an inlet aperture which providesa flow restriction to an air flow as delivered therethrough.
 3. Thedelivery device of claim 2, wherein the inlet aperture provides a seatfor a lower end of the capsule prior to delivery of an air flow throughthe flow passage.
 4. The delivery device of claim 1, wherein the flowpassage is an elongate flow passage and the capsule is oriented axiallytherealong.
 5. The delivery device of claim 1, wherein the deliverydevice is a replaceable nosepiece unit.
 6. The delivery device of claim1, wherein the powdered sumatriptan substance comprises a sumatriptanbase or sumatriptan succinate.
 7. The delivery device of claim 1,wherein the powdered sumatriptan substance contains only sumatriptansuccinate and no introduced excipients or adjuvants.
 8. The deliverydevice of claim 7, wherein the capsule contains 10 mg of sumatriptansuccinate powder.
 9. The delivery device of claim 1, wherein thepowdered sumatriptan substance has a particle size distribution of 10%less than about 10 μm, 50% less than about 30 μm and 90% less than about90 μm.
 10. A method of treating headache in a human subject, comprising:fitting a housing and a mouthpiece unit to a first delivery device ofclaim 1; piercing the capsule in the first delivery device; fitting thenosepiece of the first delivery device into a first nostril of thesubject; and the subject exhaling through the mouthpiece unit to causeclosure of the oropharyngeal velum of the subject and cause the capsuleof the first delivery device to be rotated and release the powderedsumatriptan substance from within the capsule of the first deliverydevice and be entrained in an exhaled air flow.
 11. The method of claim10, further comprising: removing the housing and the mouthpiece unitfrom the first delivery device; fitting the housing and the mouthpieceunit to a second delivery device of claim 1; piercing the capsule in thesecond delivery device; fitting the nosepiece of the second deliverydevice into a second nostril of the subject; and the subject exhalingthrough the mouthpiece unit to cause closure of the oropharyngeal velumof the subject and cause the capsule of the second delivery device to berotated and release the powdered sumatriptan substance from within thecapsule of the second delivery device and be entrained in an exhaled airflow.
 12. The method of claim 11, in the treatment of cluster headaches.13. The method of claim 11, in the treatment of migraine.
 14. The methodof claim 11, wherein piercing a capsule in the first or second deliverydevice comprises piercing the capsule at first and second spacedlocations along an axial length thereof, and the first and second spacedlocations are above a height of the powdered sumatriptan substance ascontained by the capsule.
 15. A delivery device for delivering apowdered sumatriptan substance to a nasal cavity of a human subject, thedelivery device comprising: a nosepiece for fitting to the nasal cavityof the subject, and a capsule-containing member which contains acapsule, the capsule containing the powdered sumatriptan substance to bedelivered to the nasal cavity of the subject, the powdered sumatriptansubstance containing only sumatriptan succinate and no introducedexcipients or adjuvants, wherein the capsule-containing member includesa flow passage in which the capsule is disposed to be rotatabletherewithin when an air flow is delivered therethrough, the flow passageincluding an inlet and an outlet which is in fluid communication withthe nosepiece, wherein the device is configured such that, when thenosepiece is fitted to the nasal cavity of the subject, oral exhalationby the subject through the nosepiece acts to close the velum of thesubject and drive an air flow through the nasal cavity, with the airflow passing into one nasal passage and out the other nasal passage,thereby achieving a bi-directional air flow, and wherein the powderedsumatriptan substance has a particle size distribution of 10% less thanabout 20 μm, 50% less than about 50 μm and 90% less than about 150 μm.16. The delivery device of claim 15, wherein the capsule contains 10 mgof sumatriptan succinate powder.
 17. A nasal delivery device fordelivering powdered sumatriptan to a nasal cavity of a human subject,the delivery device comprising: a nosepiece for fitting to the nasalcavity of the subject, and a capsule-containing member which contains acapsule, the capsule containing the powdered sumatriptan to be deliveredto the nasal cavity of the subject, wherein the capsule-containingmember includes a flow passage in which the capsule is disposed to berotatable therewithin when an air flow is delivered therethrough, theflow passage including an inlet and an outlet which is in fluidcommunication with the nosepiece, and wherein the device is configuredsuch that when, the nosepiece is fitted to the nasal cavity of thesubject, oral exhalation by the subject through the nosepiece acts toclose the velum of the subject and drive an air flow through the nasalcavity, with the air flow passing into one nasal passage and out theother nasal passage, thereby achieving a bi-directional air flow, andwherein the powdered sumatriptan has a particle size distribution of 10%less than about 20 μm, 50% less than about 50 μm and 90% less than about150 μm.
 18. The delivery device of claim 17, wherein the powderedsumatriptan comprises a sumatriptan base or sumatriptan succinate. 19.The delivery device of claim 17, wherein the powdered sumatriptancontains only sumatriptan succinate and no introduced excipients oradjuvants.
 20. The delivery device of claim 17, wherein the capsulecontains 10 mg of sumatriptan succinate powder.